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Genomic and Protein Expression Profiling Identifies CDK6 As Novel Independent Prognostic Marker in Medulloblastoma

From the Division of Molecular Genetics, German Cancer Research Center; Central Unit Biostatistics, German Cancer Research Center, Heidelberg; Department of Neuropathology, Heinrich Heine University, Duesseldorf, Germany; Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute, Hinxton, United Kingdom; and Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia.

Address reprint requests to Peter Lichter, PhD, German Cancer Research Center, Division of Molecular Genetics (B060), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; e-mail: m.macleod{at}dkfz.de

PURPOSE: Medulloblastoma is the most common malignant brain tumor in children. Despite multimodal aggressive treatment, nearly half of the patients die as a result of this tumor. Identification of molecular markers for prognosis and development of novel pathogenesis-based therapies depends crucially on a better understanding of medulloblastoma pathomechanisms.

PATIENTS AND METHODS: We performed genome-wide analysis of DNA copy number imbalances in 47 medulloblastomas using comparative genomic hybridization to large insert DNA microarrays (matrix-CGH). The expression of selected candidate genes identified by matrix-CGH was analyzed immunohistochemically on tissue microarrays representing medulloblastomas from 189 clinically well-documented patients. To identify novel prognostic markers, genomic findings and protein expression data were correlated to patient survival.

RESULTS: Matrix-CGH analysis revealed frequent DNA copy number alterations of several novel candidate regions. Among these, gains at 17q23.2-qter (P < .01) and losses at 17p13.1 to 17p13.3 (P = .04) were significantly correlated to poor prognosis. Within 17q23.2-qter and 7q21.2, two of the most frequently gained chromosomal regions, confined amplicons were identified that contained the PPM1D and CDK6 genes, respectively. Immunohistochemistry revealed strong expression of PPM1D in 148 (88%) of 168 and CDK6 in 50 (30%) of 169 medulloblastomas. Overexpression of CDK6 correlated significantly with poor prognosis (P < .01) and represented an independent prognostic marker of overall survival on multivariate analysis (P = .02).

CONCLUSION: We identified CDK6 as a novel molecular marker that can be determined by immunohistochemistry on routinely processed tissue specimens and may facilitate the prognostic assessment of medulloblastoma patients. Furthermore, increased protein-levels of PPM1D and CDK6 may link the TP53 and RB1 tumor suppressor pathways to medulloblastoma pathomechanisms.

Supported by Bundesministerium fr Bildungund Forschung Grants No. 01GS0460 and 01GRO417 (P.L.), and by a Kekulé-fellowship of the Fonds der Chemischen Industrie (F.M.).

Both F.M. and B.R. contributed equally to this work.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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